The long-term goals of our research are to understand the mechanisms governing growth and degenerative processes in the central nervous system. We previously advanced the hypothesis that disturbances in the regulation of mitochondrial calcium transport at the level of the rate-limiting enzyme of mitochondrial metabolism, pyruvate dehydrogenase, is a key event in the triggering of degenerative processes which follow denervation and possibly in various pathological conditions. Our previous studies have provided various means of testing this hypothesis. As in the past, the proposed experiments will take advantage of our knowledge of the various biochemical and morphological alterations (degeneration and sprouting) which follow deafferentation of the hippocampus from its main input, the entorhinal cortex. Our specific aims are (1) to identify the factors which regulate pyruvate dehydrogenase activity and mitochondrial calcium transport in intact and denervated hippocampus of rats of different ages (in particular we propose to determine the role of pyruvate carboxylase and to test the involvement of polyamines and various neuroactive peptides in the regulation of mitochondrial metabolism), (2) to study the effects of chronic insulin treatment on the morphological alterations induced in the rat hippocampus by entorhinal cortex lesions, and (3) to determine the effects of entorhinal cortex lesion on biochemical and morphological alterations in hippocampus of rats of different ages. These studies should significantly add to our understanding of the mechanisms by which presynaptic afferents participate in the regulation of intracellular calcium concentration in the target cells and possibly provide tools to manipulate growth and degenerative processes which might ultimately be applicable in a wide range of pathological conditions.